Electrical substance clearance from the brain

ABSTRACT

A method is provided that includes implanting (a) a parenchymal electrode in or in contact with an outer surface of brain parenchyma of a subject identified as at risk of or suffering from a disease, and (b) a cerebrospinal fluid (CSF) electrode in a CSF-filled space of a brain of the subject, the CSF-filled space selected from the group consisting of: a ventricular system and a subarachnoid space. A midplane treatment electrode is disposed in or over a superior sagittal sinus. Control circuitry is activated to drive the parenchymal electrode and the CSF electrode to drive a substance from the brain parenchyma into the CSF-filled space of the brain, and apply a treatment current between the CSF electrode and the midplane treatment electrode to drive the substance from the CSF-filled space of the brain to the superior sagittal sinus. Other embodiments are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is the U.S. national stage of InternationalApplication PCT/IL2016/051161, filed Oct. 27, 2016, which claimspriority from and is a continuation-in-part of U.S. application Ser. No.14/926,705, filed Oct. 29, 2015, now U.S. Pat. No. 9,724,515, which isassigned to the assignee of the present application and is incorporatedherein by reference.

FIELD OF THE APPLICATION

The present invention relates generally to treatment and prevention ofAlzheimer's disease and/or cerebral amyloid angiopathy (CAA), andspecifically to electrical techniques for treating, preventing, orslowing the progression of Alzheimer's disease and/or CAA.

BACKGROUND OF THE APPLICATION

Alzheimer's disease is a chronic neurodegenerative disease that causesdementia. Accumulation of substances such as amyloid beta and/or tauprotein in the brain is widely believed to contribute to the developmentof Alzheimer's disease.

US Patent Application Publication 2014/0324128 to Gross, which isassigned to the assignee of the present application and is incorporatedherein by reference, describes apparatus for driving fluid between firstand second anatomical sites of a subject. The apparatus comprises (1) afirst electrode, configured to be coupled to the first anatomical siteof the subject; (2) a second electrode, configured to be coupled to thesecond anatomical site of the subject; and (3) a control unit,configured to (i) detect a pressure difference between the first andsecond anatomical sites, and (ii) in response to the detected pressuredifference, drive fluid between the first and second anatomical sites byapplying a treatment voltage between the first and second electrodes.Other embodiments are also described.

SUMMARY OF THE APPLICATION

Some embodiments of the present invention provide techniques fortreating Alzheimer's disease and/or cerebral amyloid angiopathy (CAA).In some applications of the present invention, a parenchymal electrodeis implanted in parenchyma of the brain, and a cerebrospinal fluid (CSF)electrode is implanted in a CSF-filled space of the brain, e.g.,selected from a ventricular system and a subarachnoid space. Controlcircuitry is activated to drive the parenchymal and the CSF electrodesto clear a substance, such as amyloid beta and/or tau protein, from thebrain parenchyma into the CSF-filled space of the brain.

In some applications, the techniques of the present invention, inaddition to clearing the substance from the brain parenchyma into theCSF-filled space, clear the substance from the CSF-filled space to asuperior sagittal sinus of the brain.

There is therefore provided, in accordance with an inventive concept 1of the present invention, apparatus comprising:

a parenchymal electrode, configured to be implanted in brain parenchymaof a subject identified as at risk of or suffering from a disease;

a cerebrospinal fluid (CSF) electrode, configured to be implanted in aCSF-filled space of a brain of the subject, the CSF-filled spaceselected from the group consisting of: a ventricular system and asubarachnoid space; and

control circuitry, configured to drive the parenchymal and the CSFelectrodes to clear a substance from the brain parenchyma into theCSF-filled space of the brain.

There is further provided, in accordance with an inventive concept 2 ofthe present invention, apparatus comprising:

a parenchymal electrode, configured to be implanted in electricalcontact with brain parenchyma of a subject identified as at risk of orsuffering from a disease;

a cerebrospinal fluid (CSF) electrode, configured to be implanted in aCSF-filled space of a brain of the subject, the CSF-filled spaceselected from the group consisting of: a ventricular system and asubarachnoid space; and

control circuitry, configured to drive the parenchymal and the CSFelectrodes to clear a substance from the brain parenchyma into theCSF-filled space of the brain.

Inventive concept 3. The apparatus according to any one of inventiveconcepts 1-2, wherein the disease is Alzheimer's disease, and whereinthe parenchymal electrode is configured to be implanted in the subjectidentified as at risk of or suffering from Alzheimer's disease.Inventive concept 4. The apparatus according to any one of inventiveconcepts 1-2, wherein the disease is cerebral amyloid angiopathy (CAA),and wherein the parenchymal electrode is configured to be implanted inthe subject identified as at risk of or suffering from CAA.

Inventive concept 5. The apparatus according to any one of inventiveconcepts 1-2, wherein the CSF-filled space of the brain is theventricular system, and wherein the CSF electrode is a ventricularelectrode, configured to be implanted in the ventricular system.

Inventive concept 6. The apparatus according to any one of inventiveconcepts 1-2, wherein the CSF-filled space of the brain is thesubarachnoid space, and wherein the CSF electrode is a subarachnoidelectrode, configured to be implanted in the subarachnoid space.Inventive concept 7. The apparatus according to any one of inventiveconcepts 1-2, wherein the substance includes amyloid beta, and whereinthe control circuitry is configured to drive the parenchymal and the CSFelectrodes to clear the amyloid beta from the brain parenchyma into theCSF-filled space of the brain.Inventive concept 8. The apparatus according to any one of inventiveconcepts 1-2, wherein the substance includes metal ions, and wherein thecontrol circuitry is configured to drive the parenchymal and the CSFelectrodes to clear the metal ions from the brain parenchyma into theCSF-filled space of the brain.Inventive concept 9. The apparatus according to any one of inventiveconcepts 1-2, wherein the substance includes tau protein, and whereinthe control circuitry is configured to drive the parenchymal and the CSFelectrodes to clear the tau protein from the brain parenchyma into theCSF-filled space of the brain.Inventive concept 10. The apparatus according to any one of inventiveconcepts 1-2, wherein the parenchymal electrode is configured to beimplanted in white matter of the brain.Inventive concept 11. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured to configurethe parenchymal electrode to be an anode, and the CSF electrode to be acathode.Inventive concept 12. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured to configurethe parenchymal electrode to be a cathode, and the CSF electrode to bean anode.Inventive concept 13. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured toadditionally apply deep brain stimulation using the parenchymalelectrode.Inventive concept 14. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured to beimplanted under skin of the subject.Inventive concept 15. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured to drive theparenchymal and the CSF electrodes to clear the substance by applying anon-excitatory current between the parenchymal and the CSF electrodes.Inventive concept 16. The apparatus according to any one of inventiveconcepts 1-2, wherein the control circuitry is configured to drive theparenchymal and the CSF electrodes to clear the substance by applyingdirect current between the parenchymal and the CSF electrodes.Inventive concept 17. The apparatus according to inventive concept 16,wherein the control circuitry is configured to apply the direct currentwith an average amplitude of between 1 and 5 mA.Inventive concept 18. The apparatus according to inventive concept 16,wherein the control circuitry is configured to apply the direct currentwith an average amplitude of less than 1.2 V.Inventive concept 19. The apparatus according to inventive concept 16,wherein the control circuitry is configured to apply the direct currentas a series of pulses.Inventive concept 20. The apparatus according to inventive concept 19,wherein the control circuitry is configured to apply the direct currentas the series of pulses having an average pulse duration of between 100milliseconds and 300 seconds.Inventive concept 21. The apparatus according to inventive concept 19,wherein the control circuitry is configured to apply the direct currentas the series of pulses with a duty cycle of between 1% and 50%.Inventive concept 22. The apparatus according to inventive concept 19,wherein the control unit is configured to:

drive the parenchymal and the CSF electrodes to clear the substance byapplying a voltage between the parenchymal and the CSF electrodes duringeach of the pulses,

while applying the voltage, measure a current resulting from applicationof the voltage during the pulse, and

terminate the pulse upon the measured current falling below a thresholdvalue.

Inventive concept 23. The apparatus according to inventive concept 22,wherein the threshold value is based on an initial current magnitudemeasured upon commencement of the pulse.

Inventive concept 24. The apparatus according to any one of inventiveconcepts 1-2, further comprising a midplane treatment electrode, adaptedto be disposed in or over a superior sagittal sinus, wherein the controlcircuitry is configured to clear the substance from the CSF-filled spaceof the brain to the superior sagittal sinus, by applying a treatmentcurrent between the midplane treatment electrode and the CSF electrode.Inventive concept 25. The apparatus according to inventive concept 24,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus.Inventive concept 26. The apparatus according to inventive concept 25,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus, outside and in electrical contact with askull of a head of the subject.Inventive concept 27. The apparatus according to inventive concept 25,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus, under a skull of a head of the subject.Inventive concept 28. The apparatus according to inventive concept 24,wherein the midplane treatment electrode is adapted to be implanted inthe superior sagittal sinus.Inventive concept 29. The apparatus according to inventive concept 24,wherein the CSF electrode is adapted to be disposed between 1 and 12 cmof a sagittal midplane of a skull of the subject.Inventive concept 30. The apparatus according to inventive concept 24,

wherein the CSF-filled space of the brain is the subarachnoid space,

wherein the CSF electrode is a subarachnoid electrode, configured to beimplanted in the subarachnoid space, and

wherein the control circuitry is configured to clear the substance fromthe subarachnoid space to the superior sagittal sinus.

Inventive concept 31. The apparatus according to inventive concept 24,wherein the control circuitry is configured to clear the substance byelectroosmotically driving fluid from the CSF-filled space of the brainto the superior sagittal sinus.

Inventive concept 32. The apparatus according to inventive concept 31,wherein the control circuitry is configured to drive the fluid from theCSF-filled space of the brain to the superior sagittal sinus byconfiguring the midplane treatment electrode as a cathode, and the CSFelectrode as an anode.Inventive concept 33. The apparatus according to inventive concept 24,wherein the control circuitry is configured to clear the substance byelectrophoretically driving the substance from the CSF-filled space ofthe brain to the superior sagittal sinus.Inventive concept 34. The apparatus according to inventive concept 24,wherein the control circuitry is configured to apply the treatmentcurrent as direct current.Inventive concept 35. The apparatus according to inventive concept 24,wherein the control circuitry is configured to simultaneously drive (a)the parenchymal and the CSF electrodes to clear the substance from thebrain parenchyma into the CSF-filled space of the brain, and (b) applythe treatment current between the midplane treatment electrode and theCSF electrode to clear the substance from the CSF-filled space to thesuperior sagittal sinus.Inventive concept 36. The apparatus according to inventive concept 35,wherein the control circuitry is configured to apply first, second, andthird voltages to the parenchymal electrode, the CSF electrode, and themidplane treatment electrode, respectively, the third voltage morepositive than the second voltage, which is in turn more positive thanfirst voltage.Inventive concept 37. The apparatus according to inventive concept 24,wherein the control circuitry is configured to alternatingly (a) drivethe parenchymal and the CSF electrodes to clear the substance from thebrain parenchyma into the CSF-filled space of the brain, and (b) applythe treatment current between the midplane treatment electrode and theCSF electrode to clear the substance from the CSF-filled space to thesuperior sagittal sinus.Inventive concept 38. The apparatus according to any one of inventiveconcepts 1-2,

wherein the cerebrospinal fluid (CSF) electrode is a first acerebrospinal fluid (CSF) electrode,

wherein the apparatus further comprises:

-   -   a midplane treatment electrode, adapted to be disposed in or        over a superior sagittal sinus; and    -   a second cerebrospinal fluid (CSF) electrode, configured to be        implanted in a CSF-filled space of a brain of the subject, the        CSF-filled space selected from the group consisting of: a        ventricular system and a subarachnoid space, and

wherein the control circuitry is configured to clear the substance fromthe CSF-filled space of the brain to the superior sagittal sinus, byapplying a treatment current between (a) the midplane treatmentelectrode and (b) the second CSF electrode.

Inventive concept 39. The apparatus according to inventive concept 38,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus.

Inventive concept 40. The apparatus according to inventive concept 39,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus, outside and in electrical contact with askull of a head of the subject.

Inventive concept 41. The apparatus according to inventive concept 39,wherein the midplane treatment electrode is adapted to be disposed overthe superior sagittal sinus, under a skull of a head of the subject.

Inventive concept 42. The apparatus according to inventive concept 38,wherein the midplane treatment electrode is adapted to be implanted inthe superior sagittal sinus.

Inventive concept 43. The apparatus according to any one of inventiveconcepts 1-2, further comprising:

midplane treatment electrodes, adapted to be disposed over a superiorsagittal sinus; and

lateral treatment electrodes, adapted to be disposed between 1 and 12 cmof a sagittal midplane of a skull of a head of the subject,

wherein the control circuitry is configured to clear the substance fromthe subarachnoid space to the superior sagittal sinus, by applying oneor more treatment currents between (a) one or more of the midplanetreatment electrodes and (b) one or more of the lateral treatmentelectrodes.

Inventive concept 44. The apparatus according to inventive concept 43,wherein the midplane treatment electrodes are adapted to be disposedover the superior sagittal sinus, outside and in electrical contact witha skull of a head of the subject.

Inventive concept 45. The apparatus according to inventive concept 43,wherein the midplane treatment electrodes are adapted to be disposedover the superior sagittal sinus, under a skull of a head of thesubject.

Inventive concept 46. The apparatus according to inventive concept 43,wherein the control circuitry is configured to clear the substance byelectroosmotically driving fluid from the subarachnoid space to thesuperior sagittal sinus.

Inventive concept 47. The apparatus according to inventive concept 46,wherein the control circuitry is configured to configure the midplanetreatment electrodes as cathodes, and the lateral treatment electrodesas anodes.

Inventive concept 48. The apparatus according to inventive concept 46,

wherein the lateral treatment electrodes comprise (a) left lateraltreatment electrodes, which are adapted to be disposed left of thesagittal midplane of the skull, and (b) right lateral treatmentelectrodes, which are adapted to be disposed right of the sagittalmidplane of the skull, and

wherein the control circuitry is configured to configure the midplanetreatment electrodes as cathodes, and the left and the right lateraltreatment electrodes as left and right anodes, respectively.

Inventive concept 49. The apparatus according to inventive concept 43,wherein the control circuitry is configured to clear the substance byelectrophoretically driving the substance from the subarachnoid space tothe superior sagittal sinus.

Inventive concept 50. The apparatus according to inventive concept 49,

wherein the lateral treatment electrodes comprise (a) left lateraltreatment electrodes, which are adapted to be disposed left of thesagittal midplane of the skull, and (b) right lateral treatmentelectrodes, which are adapted to be disposed right of the sagittalmidplane of the skull, and

wherein the control circuitry is configured to configure the midplanetreatment electrodes as anodes, and the left and the right lateraltreatment electrodes as left and right cathodes, respectively.

Inventive concept 51. The apparatus according to inventive concept 43,wherein the lateral treatment electrodes are adapted to be implantedunder an arachnoid mater of the subject.

Inventive concept 52. The apparatus according to inventive concept 51,wherein the lateral treatment electrodes are adapted to be disposed inthe subarachnoid space.

Inventive concept 53. The apparatus according to inventive concept 51,wherein the lateral treatment electrodes are adapted to be disposed ingray or white matter of a brain of the subject.

Inventive concept 54. The apparatus according to inventive concept 43,wherein the control circuitry is configured to apply the one or moretreatment currents as direct currents.

There is still further provided, in accordance with an inventive concept55 of the present invention, a method comprising:

implanting a parenchymal electrode in electrical contact with brainparenchyma of a subject identified as at risk of or suffering from adisease;

implanting a cerebrospinal fluid (CSF) electrode in a CSF-filled spaceof a brain of the subject, the CSF-filled space selected from the groupconsisting of: a ventricular system and a subarachnoid space; and

activating control circuitry to drive the parenchymal and the CSFelectrodes to clear a substance from the brain parenchyma into theCSF-filled space of the brain.

Inventive concept 56. The method according to inventive concept 55,wherein the disease is Alzheimer's disease, and wherein implantingparenchymal electrode comprises implanting the parenchymal electrode inthe subject identified as at risk of or suffering from Alzheimer'sdisease.Inventive concept 57. The method according to inventive concept 55,wherein the disease is cerebral amyloid angiopathy (CAA), and whereinimplanting parenchymal electrode comprises implanting the parenchymalelectrode in the subject identified as at risk of or suffering from CAA.Inventive concept 58. The method according to inventive concept 55,wherein the CSF-filled space of the brain is the ventricular system,wherein the CSF electrode is a ventricular electrode, and whereinactivating the control circuitry comprises activating the controlcircuitry to drive the parenchymal and the ventricular electrodes toclear the substance from the brain parenchyma into the ventricularsystem.Inventive concept 59. The method according to inventive concept 55,wherein the CSF-filled space of the brain is the subarachnoid space,wherein the CSF electrode is a subarachnoid electrode, and whereinactivating the control circuitry comprises activating the controlcircuitry to drive the parenchymal and the subarachnoid electrodes toclear the substance from the brain parenchyma into the subarachnoidspace.Inventive concept 60. The method according to inventive concept 55,wherein the substance includes amyloid beta, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal and the CSF electrodes to clear the amyloid beta fromthe brain parenchyma into the CSF-filled space of the brain.Inventive concept 61. The method according to inventive concept 55,wherein the substance includes metal ions, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal and the CSF electrodes to clear the metal ions from thebrain parenchyma into the CSF-filled space of the brain.Inventive concept 62. The method according to inventive concept 55,wherein the substance includes tau protein, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal and the CSF electrodes to clear the tau protein from thebrain parenchyma into the CSF-filled space of the brain.Inventive concept 63. The method according to inventive concept 55,wherein implanting the parenchymal electrode in electrical contact withthe brain parenchyma comprises implanting the parenchymal electrode inthe brain parenchyma.Inventive concept 64. The method according to inventive concept 63,wherein implanting the parenchymal electrode in the brain parenchymacomprises implanting the parenchymal electrode in white matter of thebrain.Inventive concept 65. The method according to inventive concept 63,wherein implanting the parenchymal and the CSF electrodes comprisesimplanting the parenchymal and the CSF electrodes such that an area ofbuild-up of the substance is between the parenchymal and the CSFelectrodes.Inventive concept 66. The method according to inventive concept 65,wherein implanting the parenchymal and the CSF electrodes comprisesidentifying the area of build-up of the substance in the brainparenchyma before implanting the parenchymal and the CSF electrodes.Inventive concept 67. The method according to inventive concept 66,wherein identifying the area of build-up comprises performing imaging ofthe brain.Inventive concept 68. The method according to inventive concept 67,wherein performing the imaging comprises performing functional MRI(fMRI) imaging of the brain.Inventive concept 69. The method according to inventive concept 63,wherein implanting the parenchymal electrode comprises implanting theparenchymal electrode such that an area of build-up of the substance isbetween the parenchymal electrode and an area of the CSF-filled space ofthe brain nearest the area of build-up.Inventive concept 70. The method according to inventive concept 69,wherein implanting the parenchymal electrode comprises identifying thearea of build-up of the substance in the brain parenchyma beforeimplanting the parenchymal electrode.Inventive concept 71. The method according to inventive concept 70,wherein identifying the area of build-up comprises performing imaging ofthe brain.Inventive concept 72. The method according to inventive concept 71,wherein performing the imaging comprises performing functional MRI(fMRI) imaging of the brain.Inventive concept 73. The method according to inventive concept 55,wherein activating the control circuitry comprises activating thecontrol circuitry to configure the parenchymal electrode to be an anode,and the CSF electrode to be a cathode.Inventive concept 74. The method according to inventive concept 55,wherein activating the control circuitry comprises activating thecontrol circuitry to configure the parenchymal electrode to be acathode, and the CSF electrode to be an anode.Inventive concept 75. The method according to inventive concept 55,further comprising applying deep brain stimulation using the parenchymalelectrode.Inventive concept 76. The method according to inventive concept 55,further comprising implanting the control circuitry under skin of thesubject.Inventive concept 77. The method according to inventive concept 55,wherein activating the control circuitry to drive the parenchymal andthe CSF electrodes comprises activating the control circuitry to drivethe parenchymal and the CSF electrodes to clear the substance byapplying a non-excitatory current between the parenchymal and the CSFelectrodes.Inventive concept 78. The method according to inventive concept 55,wherein activating the control circuitry to drive the parenchymal andthe CSF electrodes comprises activating the control circuitry to drivethe parenchymal and the CSF electrodes to clear the substance byapplying direct current between the parenchymal and the CSF electrodes.Inventive concept 79. The method according to inventive concept 78,wherein activating the control circuitry to apply the direct currentcomprises activating the control circuitry to apply the direct currentwith an average amplitude of between 1 and 5 mA.Inventive concept 80. The method according to inventive concept 78,wherein activating the control circuitry to apply the direct currentcomprises activating the control circuitry to apply the direct currentwith an average amplitude of less than 1.2 V.Inventive concept 81. The method according to inventive concept 78,wherein activating the control circuitry to apply the direct currentcomprises activating the control circuitry to apply the direct currentas a series of pulses.Inventive concept 82. The method according to inventive concept 81,wherein activating the control circuitry to apply the direct current asthe series of pulses comprises activating the control circuitry to applythe direct current as the series of pulses having an average pulseduration of between 100 milliseconds and 300 seconds.Inventive concept 83. The method according to inventive concept 81,wherein activating the control circuitry to apply the direct current asthe series of pulses comprises activating the control circuitry to applythe direct current as the series of pulses with a duty cycle of between1% and 50%.Inventive concept 84. The method according to inventive concept 81,wherein activating the control circuitry to drive the parenchymal andthe CSF electrodes comprises activating the control unit to:

drive the parenchymal and the CSF electrodes to clear the substance byapplying a voltage between the parenchymal and the CSF electrodes duringeach of the pulses,

while applying the voltage, measure a current resulting from applicationof the voltage during the pulse, and

terminate the pulse upon the measured current falling below a thresholdvalue.

Inventive concept 85. The method according to inventive concept 84,wherein the threshold value is based on an initial current magnitudemeasured upon commencement of the pulse.

Inventive concept 86. The method according to inventive concept 55,

further comprising disposing a midplane treatment electrode in or over asuperior sagittal sinus,

wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance from the CSF-filled space ofthe brain to the superior sagittal sinus, by applying a treatmentcurrent between the midplane treatment electrode and the CSF electrode.

Inventive concept 87. The method according to inventive concept 86,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus.

Inventive concept 88. The method according to inventive concept 87,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus,outside and in electrical contact with a skull of a head of the subject.Inventive concept 89. The method according to inventive concept 87,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus, undera skull of a head of the subject.Inventive concept 90. The method according to inventive concept 86,wherein disposing the midplane treatment electrode comprises implantingthe midplane treatment electrode in the superior sagittal sinus.Inventive concept 91. The method according to inventive concept 86,wherein implanting the CSF electrode comprises implanting the CSFelectrode between 1 and 12 cm of a sagittal midplane of a skull of thesubject.Inventive concept 92. The method according to inventive concept 86,

wherein the CSF-filled space of the brain is the subarachnoid space,

wherein the CSF electrode is a subarachnoid electrode, and

wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance from the subarachnoid space tothe superior sagittal sinus.

Inventive concept 93. The method according to inventive concept 86,wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance by electroosmotically drivingfluid from the CSF-filled space of the brain to the superior sagittalsinus.Inventive concept 94. The method according to inventive concept 93,wherein activating the control circuitry comprises activating thecontrol circuitry to drive the fluid from the CSF-filled space of thebrain to the superior sagittal sinus by configuring the midplanetreatment electrode as a cathode, and the CSF electrode as an anode.Inventive concept 95. The method according to inventive concept 86,wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance by electrophoretically drivingthe substance from the CSF-filled space of the brain to the superiorsagittal sinus.Inventive concept 96. The method according to inventive concept 86,wherein activating the control circuitry comprises activating thecontrol circuitry to apply the treatment current as direct current.Inventive concept 97. The method according to inventive concept 86,wherein activating the control circuitry comprises activating thecontrol circuitry to simultaneously drive (a) the parenchymal and theCSF electrodes to clear the substance from the brain parenchyma into theCSF-filled space of the brain, and (b) apply the treatment currentbetween the midplane treatment electrode and the CSF electrode to clearthe substance from the CSF-filled space to the superior sagittal sinus.Inventive concept 98. The method according to inventive concept 97,wherein activating the control circuitry comprises activating thecontrol circuitry to apply first, second, and third voltages to theparenchymal electrode, the CSF electrode, and the midplane treatmentelectrode, respectively, the third voltage more positive than the secondvoltage, which is in turn more positive than first voltage.Inventive concept 99. The method according to inventive concept 86,wherein activating the control circuitry comprises activating thecontrol circuitry to alternatingly (a) drive the parenchymal and the CSFelectrodes to clear the substance from the brain parenchyma into theCSF-filled space of the brain, and (b) apply the treatment currentbetween the midplane treatment electrode and the CSF electrode to clearthe substance from the CSF-filled space to the superior sagittal sinus.Inventive concept 100. The method according to inventive concept 55,

wherein the cerebrospinal fluid (CSF) electrode is a first acerebrospinal fluid (CSF) electrode,

wherein the method further comprises:

-   -   disposing a midplane treatment electrode in or over a superior        sagittal sinus; and    -   implanting a second cerebrospinal fluid (CSF) electrode in a        CSF-filled space of a brain of the subject, the CSF-filled space        selected from the group consisting of: a ventricular system and        a subarachnoid space, and

wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance from the CSF-filled space ofthe brain to the superior sagittal sinus, by applying a treatmentcurrent between (a) the midplane treatment electrode and (b) the secondCSF electrode.

Inventive concept 101. The method according to inventive concept 100,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus.

Inventive concept 102. The method according to inventive concept 101,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus,outside and in electrical contact with a skull of a head of the subject.Inventive concept 103. The method according to inventive concept 101,wherein disposing the midplane treatment electrode comprises disposingthe midplane treatment electrode over the superior sagittal sinus, undera skull of a head of the subject.Inventive concept 104. The method according to inventive concept 100,wherein disposing the midplane treatment electrode comprises implantingthe midplane treatment electrode in the superior sagittal sinus.Inventive concept 105. The method according to inventive concept 55,further comprising:

disposing midplane treatment electrodes over a superior sagittal sinus;and

disposing lateral treatment electrodes between 1 and 12 cm of a sagittalmidplane of a skull of a head of the subject,

wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance from the subarachnoid space tothe superior sagittal sinus, by applying one or more treatment currentsbetween (a) one or more of the midplane treatment electrodes and (b) oneor more of the lateral treatment electrodes.

Inventive concept 106. The method according to inventive concept 105,wherein disposing the midplane treatment electrodes comprises disposingthe midplane treatment electrodes over the superior sagittal sinus,outside and in electrical contact with a skull of a head of the subject.Inventive concept 107. The method according to inventive concept 105,wherein disposing the midplane treatment electrodes comprises disposingthe midplane treatment electrodes over the superior sagittal sinus,under a skull of a head of the subject.Inventive concept 108. The method according to inventive concept 105,wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance by electroosmotically drivingfluid from the subarachnoid space to the superior sagittal sinus.Inventive concept 109. The method according to inventive concept 108,wherein activating the control circuitry comprises activating thecontrol circuitry to configure the midplane treatment electrodes ascathodes, and the lateral treatment electrodes as anodes.Inventive concept 110. The method according to inventive concept 108,

wherein the lateral treatment electrodes include left lateral treatmentelectrodes and right lateral treatment electrodes,

wherein disposing the lateral treatment electrodes includes disposingthe left lateral treatment electrodes left of the sagittal midplane ofthe skull, and disposing the right lateral treatment electrodes right ofthe sagittal midplane of the skull, and

wherein activating the control circuitry includes activating the controlcircuitry to configure the midplane treatment electrodes as cathodes,and the left and the right lateral treatment electrodes as left andright anodes, respectively

Inventive concept 111. The method according to inventive concept 105,wherein activating the control circuitry comprises activating thecontrol circuitry to clear the substance by electrophoretically drivingthe substance from the subarachnoid space to the superior sagittalsinus.Inventive concept 112. The method according to inventive concept 111,

wherein the lateral treatment electrodes include left lateral treatmentelectrodes and right lateral treatment electrodes,

wherein disposing the lateral treatment electrodes includes disposingthe left lateral treatment electrodes left of the sagittal midplane ofthe skull, and disposing the right lateral treatment electrodes right ofthe sagittal midplane of the skull, and

wherein activating the control circuitry includes activating the controlcircuitry to configure the midplane treatment electrodes as anodes, andthe left and the right lateral treatment electrodes as left and rightcathodes, respectively.

Inventive concept 113. The method according to inventive concept 105,wherein disposing the lateral treatment electrodes comprises implantingthe lateral treatment electrodes under an arachnoid mater of thesubject.

Inventive concept 114. The method according to inventive concept 113,wherein disposing the lateral treatment electrodes comprises disposingthe lateral treatment electrodes in the subarachnoid space.

Inventive concept 115. The method according to inventive concept 113,wherein disposing the lateral treatment electrodes comprises disposingthe lateral treatment electrodes in gray or white matter of a brain ofthe subject.

Inventive concept 116. The method according to inventive concept 105,wherein activating the control circuitry comprises activating thecontrol circuitry to apply the one or more treatment currents as directcurrents.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are schematic illustrations of a system for treatingAlzheimer's disease, in accordance with respective applications of thepresent invention;

FIGS. 2A-B are schematic illustrations of cross-sections of a rat brainshowing results of an animal experiment performed in accordance with anapplication of the present invention;

FIG. 3 is a graph showing results of an in vitro experiment performed inaccordance with an application of the present invention; and

FIGS. 4A-G are schematic illustrations of alternative configurations ofthe system of FIGS. 1A-C, in accordance with respective applications ofthe present invention.

DETAILED DESCRIPTION OF APPLICATIONS

FIGS. 1A-C are schematic illustrations of a system 20 for treatingAlzheimer's disease and/or cerebral amyloid angiopathy (CAA), inaccordance with respective applications of the present invention. System20 comprises parenchymal and cerebrospinal fluid (CSF) electrodes 30 and32, and control circuitry 34, which is electrically coupled toparenchymal and CSF electrodes 30 and 32, typically by parenchymal andCSF electrode leads 36 and 38, respectively.

In some applications of the present invention, as shown for two ofparenchymal electrodes 30 illustrated in FIG. 1A, parenchymal electrode30 is implanted in parenchyma 50 of a brain 52 of a subject identifiedas at risk of or suffering from Alzheimer's disease and/or from CAA,e.g., using surgical techniques similar to those used for implantationof electrodes for deep brain stimulation. Alternatively, parenchymalelectrode 30 is implanted elsewhere in the subject in electrical contactwith brain parenchyma 50, such as on and in contact with an outersurface of brain 52, as shown for the middle parenchymal electrode 30illustrated in FIG. 1A. CSF electrode 32 is implanted in a CSF-filledspace of the brain, such as ventricular system 54 of brain 52 or asubarachnoid space 144 (labeled in FIGS. 4A-G) (e.g., cisterns ofsubarachnoid space 144). For example, CSF electrode 32 may be implantedusing techniques known for implanting hydrocephalus shunts, mutatismutandis. As used in the present application, including in the claims,ventricular system 54 includes and is limited to lateral ventricles 55(left and right lateral ventricles 55A and 55B), a third ventricle 56, afourth ventricle 57, a cerebral aqueduct 59 (labeled in FIGS. 4A-G),interventricular foramina, a median aperture, and left and right lateralapertures.

Control circuitry 34 is activated to drive parenchymal and CSFelectrodes 30 and 32 to clear a substance from brain parenchyma 50 intothe CSF-filled space, such as ventricular system 54. For someapplications, the substance comprises amyloid beta, metal ions, a tauprotein, and/or a waste substance. As used in the present application,including in the claims, clearing a substance from the brain parenchymais to be understood as including clearing a portion of the substance,without clearing all of the substance. Typically, in order to clear thesubstance, control circuitry 34 applies a voltage or a current betweenparenchymal and CSF electrodes 30 and 32 (i.e., control circuitry 34regulates the voltage or the current).

Typically, a healthcare worker, such as a physician, activates controlcircuitry 34 to provide the functions described herein. Activating thecontrol unit may include configuring parameters and/or functions of thecontrol circuitry (such as using a separate programmer or externalcontroller), or activating the control unit to perform functionspreprogrammed in the control circuitry. Control circuitry 34 typicallycomprises appropriate memory, processor(s), and hardware runningsoftware that is configured to provide the functionality of controlcircuitry described herein.

Current may flow generally through tissue that is located betweenparenchymal and CSF electrodes 30 and 32. Alternatively or additionally,at least a portion of the current may flow between (a) parenchymalelectrode 30 and (b) an area of the CSF-filled space (e.g., ventricularsystem 54) nearest parenchymal electrode 30. The inventors haveappreciated that because of the low electrical resistance ofcerebrospinal fluid (CSF) in the CSF-filled space, such as ventricularsystem 54, the ventricles are to some extent a single entityelectrically. Therefore, a large portion of the current flows to thenearest portion of ventricular system 54, even if CSF electrode 32 isimplanted in a ventricle remote from parenchymal electrode 30. Forexample, as shown in FIG. 1B, if a parenchymal electrode 30A isimplanted in a right hemisphere of brain 52, most of the current mayflow between parenchymal electrode 30A and an area 58 of right ventricle55B nearest parenchymal electrode 30A, even though CSF electrode 32 isimplanted in left ventricle 55A.

For some applications, the voltage applied between the electrodes mayclear the substance electrophoretically, because of a positive ornegative charged interface between the surface of the particles of thesubstance and the surrounding brain tissue fluids. For theseapplications, the voltage applied between the electrodes causes apotential difference between brain parenchyma 50 and the CSF-filledspace, such as ventricular system 54, which causes movement of thesubstance from brain parenchyma 50 to the CSF-filled space, such asventricular system 54. Alternatively or additionally, for someapplications, the voltage applied between the electrodes may clear thesubstance electroosmotically, because of a positive or negative chargeof fluid in the parenchyma. For these applications, the voltage appliedbetween the electrodes causes a potential difference between brainparenchyma 50 and the CSF-filled space, such as ventricular system 54,which causes increased flow from brain parenchyma 50 to the CSF-filledspace, such as ventricular system 54, and thus increased transport ofthe substance from parenchyma 50 to the CSF-filled space, such asventricular system 54.

For some applications, system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of CSF electrodes 32. Parenchymalelectrodes 30 may be implanted in one or both hemispheres of brain 52,and/or at one or more than one location in each of the hemispheres. Forsome applications, such as shown in FIGS. 1A-C, system 20 comprises aplurality of parenchymal electrodes 30 and exactly one CSF electrode 32.For example, the single CSF electrode 32 may be implanted in one oflateral ventricles 55 or third ventricle 56, which, as discussed above,are to a large degree in good electrical connectivity with the otherventricles. For other applications (configuration not shown), system 20comprises (a) exactly two CSF electrodes 32, which are implanted in leftand right lateral ventricles 55A and 55B, respectively, or (b) exactlythree CSF electrodes 32, which are implanted in left and right lateralventricles 55A and 55B and third ventricle 56, respectively.

For applications in which system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of CSF electrodes 32, system 20typically comprises a corresponding plurality of parenchymal electrodeleads 36 and/or a corresponding plurality of CSF electrode leads 38.Each of the leads may comprise separate electrical insulation, and/or aportion of the leads may be joined and share common electricalinsulation, as shown in FIGS. 1A-C for parenchymal electrode leads 36.Control circuitry 34 may be activated to independently drive parenchymalelectrodes 30, e.g., using separately circuitry. Alternatively, one ormore of parenchymal electrodes 30 may be shorted to one another, suchthat the control circuitry drives the shorted electrodes together.Control circuitry 34 may be activated to drive parenchymal electrodes 30simultaneously or at different times.

For some applications, brain parenchyma 50 in which parenchymalelectrode 30 is implanted comprises white matter of the brain.

As used in the present application, including the claims, “treating”includes both treating a subject already diagnosed with Alzheimer'sdisease and/or CAA (such as by delaying, slowing, or reversingprogression of the disease, e.g., in a patient diagnosed at an earlystage), as well as preventing the development of Alzheimer's diseaseand/or CAA in a subject not diagnosed with the disease and/orasymptomatic for the disease. For example, the techniques describedherein may be used to prevent or delay the development of Alzheimer'sdisease and/or CAA in responsive to detection of an abnormal level ofamyloid beta, such as using a blood test or a spinal tap.

For some applications, control circuitry 34 is configured to beimplanted subcutaneously, such under skin of the skull of the subject ifthe housing containing the control circuitry is small, or elsewhere inthe subject's body, such as in the upper chest, if the housing of thecontrol circuitry is larger (e.g., includes batteries), with leadsthrough the neck, or optionally in the head. For these applications,control circuitry 34 is typically driven by an external controller thatis in wireless or wired communication with control circuitry 34. Forsome applications, the external controller is mounted on a bed of thesubject (e.g., disposed within a mattress), and is configured toactivate control circuitry 34 only at night, and/or only when thesubject is sleeping. Such nighttime activation may to some degree mimicthe natural timing of clearance of the substance (e.g., amyloid beta ortau protein) during sleep, during which the extracellular spaces arewider than during wakefulness, which allows more interstitial fluid(ISF) flow within the brain. For other applications, control circuitry34 is configured to be disposed externally to the subject.

For some applications, control circuitry 34 is activated to driveparenchymal and CSF electrodes 30 and 32 to clear the substance byapplying a non-excitatory current between parenchymal and CSF electrodes30 and 32, i.e., the current does not cause propagation of actionpotentials. Thus, in these applications, control circuitry 34 isactivated to set parameters of the current such that the current doesnot affect, or only minimally affects, neuronal activity. Alternatively,the applied current does excite brain tissue, such as to a small extent.

For some applications, control circuitry 34 is activated to driveparenchymal and CSF electrodes 30 and 32 to clear the substance byapplying direct current (DC) between parenchymal and CSF electrodes 30and 32. As used in the present application, including in the claims,direct current means a current having a constant polarity; the amplitudeof the direct current may or may not vary over time, and may sometimesbe zero.

For some applications, control circuitry 34 is activated to apply thedirect current with an average amplitude of at least 1 mA, no more than5 mA, and/or between 1 and 5 mA. Alternatively or additionally, for someapplications, control circuitry 34 is activated to apply the directcurrent with an average amplitude of less than 1.2 V (such an amplitudemay avoid electrolysis in the vicinity of one or both of theelectrodes).

For some applications, such as when the substance is amyloid beta,control circuitry 34 is activated to configure parenchymal electrode 30to be a cathode, and CSF electrode 32 to be an anode. Alternatively,control circuitry 34 is activated to configure parenchymal electrode 30to be an anode, and CSF electrode 32 to be a cathode. For applicationsin which the voltage applied between the electrodes clears the substanceelectrophoretically, the selected polarity of the electrodes typicallydepends on whether the substance has a positive or negative effectivecharge. Similarly, for applications in which the voltage applied betweenthe electrodes clears the substance electroosmotically, the selectedpolarity of the electrodes typically depends on whether the fluid has apositive or negative effective charge.

For some applications, control circuitry 34 is activated to apply thedirect current as a series of pulses. For some applications, the seriesof pulses has an average pulse duration of at least 10 milliseconds, nomore than 300 seconds, and/or between 10 milliseconds and 300 seconds,such as: (a) at least 10 milliseconds, no more than 100 milliseconds,and/or between 10 and 100 milliseconds, (b) at least 100 milliseconds,no more than 300 seconds (e.g., no more than 500 milliseconds), and/orbetween 100 and 300 seconds (e.g., between 100 and 500 milliseconds),(c) at least 500 milliseconds, no more than 5 seconds, and/or between500 milliseconds and 5 seconds, (d) at least 5 seconds, no more than 10seconds, and/or between 5 and 10 seconds, or (e) at least 10 seconds, nomore than 100 seconds, and/or between 10 and 100 seconds. For someapplications, the pulses are applied at a frequency of at least 0.001Hz, no more than 1 kHz, and/or between 0.001 and 1 kHz, such as: (a) atleast 100 Hz, no more than 1 kHz, and/or between 100 Hz and 1 kHz, (b)at least 20 Hz, no more than 100 Hz, and/or between 20 and 100 Hz, or(c) at least 1 Hz, no more than 10 Hz, and/or between 1 and 10 Hz.Alternatively or additionally, for some applications, the series ofpulses has a duty cycle of at least 1%, no more than 50%, and/or between1% and 50%, such as: (a) at least 1%, no more than 5%, and/or between 1%and 5%, (b) at least 5%, no more than 10%, and/or between 5% and 10%,(c) at least 10%, no more than 25%, and/or between 10% and 25%, or (d)at least 25%, no more than 50%, and/or between 25% and 50%. Typically,but not necessarily, the duty cycle is no more than 90%, because a givenlevel of applied voltage produces higher current in the tissue if thecapacitance in the tissue is allowed to discharge between pulses.

For some of the applications in which control circuitry 34 applies avoltage between parenchymal and CSF electrodes 30 and 32 in a series ofDC pulses, the resulting current decays because of the effects of tissueelectrolytes. The current may decay by about two-thirds of its initialmagnitude within tens of milliseconds after commencement of applicationof each pulse. In order to overcome this capacitance effect, controlcircuitry 34 is activated to apply the voltage intermittently, in orderto provide time periods between pulses during which the capacitancedischarges.

For some applications, control circuitry 34 is activated to apply thevoltage intermittently with a preprogrammed frequency and/or duty cycle.These parameters may be (a) applicable to all patients or a subgroup ofpatients, (b) set during a calibration procedure upon implantation ofthe electrodes, or (c) set based on a geometry of placement ofparenchymal and/or CSF electrodes 30 and/or 32. Alternatively, controlcircuitry 34 is configured to set these parameters in real time bysensing the current resulting from the applied voltage.

For some applications, control circuitry 34 is activated to measure thecurrent resulting from the applied voltage during each of the appliedpulses, and to terminate each of the applied pulses when the magnitudeof the measured current falls below a threshold value. For example, thethreshold value may be a preprogrammed constant, or may be based on(e.g., a percentage of) the initial current magnitude measured uponcommencement of the respective pulse. Control circuitry 34 waits duringa discharge period before applying the next pulse.

For some applications, control circuitry 34 is activated to apply,between parenchymal and CSF electrodes 30 and 32, alternating current(AC) in:

-   -   a primary subset of the pulses at a primary polarity selected to        electrophoretically and/or electroosmotically clear the        substance, at a primary voltage and with a primary average pulse        duration, and    -   a secondary subset of the pulses at a secondary polarity        opposite the primary polarity, at a secondary voltage less than        the primary voltage, and with a secondary average pulse duration        greater than the primary average pulse duration.

Because of the lower secondary voltage, the secondary subset of thepulses to a large extent does not reverse the clearance of the substanceachieved during application of the primary subset of the pulses. Thistechnique may also help avoid electrolysis in the vicinity of one orboth of the electrodes, even if the primary voltage is higher than athreshold DC voltage (e.g., 1.2 V) that might otherwise causeelectrolysis.

For some applications, such as illustrated in FIG. 1C, parenchymal andCSF electrodes 30 and 32 are implanted such that one or more areas ofbuild-up 64 of the substance in brain parenchyma 50 is between theelectrodes, rather than implanting parenchymal electrode 30 within thearea of build-up. For example, the area(s) of build-up may includeamyloid plaque and/or tau protein-related nerve tissue tangles. To thisend, typically the area of build-up is first identified, for example byperforming imaging of brain 52, such as MRI (e.g., functional MRI(fMRI)) or PET imaging of brain 52. As mentioned above, a plurality ofparenchymal electrodes 30 and/or a plurality of CSF electrodes 32 may beimplanted, such as if there is more than one area of build-up 64 of thesubstance.

For some applications, also such as illustrated in FIG. 1C, the one ormore parenchymal electrode are implanted such that the one or more areasof build-up 64 are between parenchymal electrode 30A and respectiveareas 80 of the CSF-filled space, such as ventricular system 54, nearestareas of build-up 64. CSF electrode 32 may or may not be implanted nearareas 80. For applications in which CSF electrode 32 is not implantednear areas 80, the substance of area of build-up 64 may still be driveninto nearest areas 80 of the CSF-filled space, such as ventricularsystem 54, because nearest areas 80 are in fluid communication with CSFelectrode 32 via CSF of the CSF-filled space, such as ventricular system54, as discussed above. As mentioned above, a plurality of parenchymalelectrodes 30 and/or a plurality of CSF electrodes 32 may be implanted,such as if there is more than one area of build-up 64 of the substance,or in general in order to provide good clearance of the substance.

For some applications, parenchymal electrode 30 is further used forapplying deep brain stimulation, as is known in the art. For example,the deep brain stimulation may be applied when the electrodes are notbeing driven to drive the substance into the CSF-filled space, such asthe ventricular system. As is known in the art, the deep brainstimulation may be applied to reduce tremor and block involuntarymovements in patients with motion disorders, such as Parkinson'sdisease, or to treat epilepsy, cluster headaches, Tourette syndrome,chronic pain, or major depression. The implantation location ofparenchymal electrode 30 may be selected to be appropriate for thetreatment of a particular condition, as well as for clearing thesubstance.

For some applications, control circuitry 34 is activated to driveparenchymal and CSF electrodes 30 and 32 in sessions, each of which hasa duration of several seconds or several minutes, or continuously forlonger periods (e.g., 30 minutes). For some applications, the electrodesare not driven for a period that is at least an hour. Optionally,control circuitry 34 is activated to drive the electrodes only when thesubject is sleeping, such as to take advantage of the widening ofextracellular spaces and/or to inhibit any sensations that may beassociated with the driving. For example, control circuitry 34 may beactivated to use one or more of the electrodes as EEG electrodes todetect sleep. For some applications, power for activating and/orcharging control circuitry 34 is transmitted from a wireless energytransmitter in a device applied to the head, such as a hat, or from awireless energy transmitter in, under, or above a mattress, such asdescribed hereinabove. For some applications, control circuitry 34 isactivated to drive the electrodes according to a pre-selected schedule,such as a duty cycle, such as for a few hours per day. For example,control circuitry 34 may be configured to be controlled and/or poweredby an extracorporeal control circuitry, such as a control circuitrycomprising a wireless transmitter, disposed in and/or in the vicinity ofthe subject's bed. For some applications, one or more rest periodsduring which the control circuitry does not drive the electrodes areprovided in the pre-selected schedule.

For any of the applications described herein, CSF electrode 32 may beimplanted in one of the following sites, rather than in ventricularsystem 54:

-   -   a central canal of the spinal cord (which is in fluid        communication with ventricular system 54); or    -   a subarachnoid space 144 (labeled in FIGS. 4A-G) (which is in        fluid communication with ventricular system 54 because CSF        drains into cisterns of subarachnoid space 144 via foramina of        ventricular system 54).

For some applications, instead of implanting CSF electrode 32 inventricular system 54, an electrode is implanted in superior sagittalsinus 142 (labeled in FIGS. 4A-G).

For any of the applications described herein, parenchymal electrode 30may be implanted in superior sagittal sinus 142, rather than in brainparenchyma 50 (typically, in these applications, CSF electrode 32 isimplanted in ventricular system 54).

Reference is again made to FIGS. 1A-C. For some applications, controlcircuitry 34 is configured to detect a voltage difference betweenparenchyma 50 and the CSF-filled space, and set a level of the voltageapplied between parenchymal and cerebrospinal fluid (CSF) electrodes 30and 32 responsively to the detected voltage difference.

Reference is now made to FIGS. 2A-B, which are schematic illustrationsof cross-sections of a rat brain showing results of an animal experimentperformed in accordance with an application of the present invention. Arat was anesthetized, a first electrode 130 (a piece of Pt—Ir wiresoldered to a miniature connector) was inserted through a hole into thesagittal sinus, and a second electrode 132 (a pieces of Pt—Ir wiresoldered to a small electronic connector) was inserted through a hole indura mater into the right lateral ventricle.

As shown in FIG. 2A, bromophenol blue dye was stereotaxically deliveredinto both hemispheres of the rat brain at designated coordinates 120 and122. By using the left hemisphere as a diffusion control, thisexperimental setup allowed pairwise comparisons within the same animal,thereby ruling out any other effects that might effect a directedmigration of the dye in the brain.

Control circuitry was activated to apply a constant-polarity (DC)current to only the right hemisphere, between first and secondelectrodes 130 and 132, configuring first electrode 130 as a cathode andsecond electrode 132 as an anode, because bromophenol blue dye compriseseffectively anionic (negatively-charged) molecules. The current wasapplied by repeatedly alternating between two modes: (a) a first mode,in which the current was applied continuously for 5 minutes at amagnitude of 1-2 mA, and (b) a second mode, in which the current wasapplied in 10-ms-duration pulses, one pulse per second (i.e., a pulsefrequency of 1 Hz), at a magnitude of 1-2 mA.

FIG. 2B shows the displacement of the bromophenol blue dye afterapplication of the current to the right hemisphere. As can be seen, thebromophenol blue dye in the left hemisphere experienced minimaldispersion and no directed displacement. In contrast, in the righthemisphere, the applied current moved the bromophenol blue dye towardthe lateral ventricle. The dye moved with the average velocity of0.28+/−0.006 mm/min, which was more than 14 times greater than theobserved diffusion rate in the left hemisphere. In the right hemisphere,the linear displacement of the dye profile center was about 1.9±0.08 mm,while the front of the dye profile reached a maximum distance of about2.81±0.07 mm from the center of the injection point.

The results of this experiment demonstrated that molecules of dye can bemoved within brain tissue by applying a DC current using two electrodesimplanted in the brain, and that in such a setup, a natural migrationpath is toward the ventricles. The inventors believe that application ofthe current between the electrodes may have moved the dyeelectrophoretically. The inventors also believe that implantation of thefirst electrode directly in brain parenchyma, rather than in thesuperior sagittal sinus, may provide even better current-driven movementof molecules, because the resistance of the parenchyma-sinus interfacewas calculated as more than two-fold higher than the resistance measuredwithin the parenchyma, based on data collected during the experiment.

Amyloid Beta Mobility and Directionality Assessment

Reference is now made to FIG. 3, which is a graph showing results of anin vitro experiment performed in accordance with an application of thepresent invention. The experiment assessed the extent to whichapplication of direct current (DC) eliminated amyloid beta peptides froman artificial cerebrospinal fluid (aCSF) solution (comprising phosphatebuffered saline (PBS) solution). Pt—Ir electrodes were inserted into acompartment filled with the aCSF solution. Fluorophore-tagged amyloidbeta peptides were dissolved to three different dilution levels (2:500,5:500, and 10:500). Constant DC currents of three different durations(5, 10, and 15 minutes) were applied from a 1.5 V alkaline battery tothe aCSF solution containing the fluorophore-tagged amyloid betapeptides. The directionality and overall capability of amyloid beta toundergo electrophoretic movement was assessed by densitometric analysisof fluorescence on each electrode.

The fluorescence intensity was measured at both electrodes, and thefluorescence intensity was normalized at the positively-chargedelectrode (anode) with respect to the negatively-charged electrode(cathode) by taking the ratio of fluorescence. Data was averaged fromall the measurements and is presented as mean and standard error of meanin FIG. 3.

As can be seen in FIG. 3, current-duration-dependent enhancement offluorescence was observed near the positively-charged electrode (anode)(for the 2:500 dilution level). The difference in fluorescence betweenthe anodes and the cathodes was statistically significant (one tailedt-test: p<10^-15; t=12.17) for the current-duration-dependent analysis.The current-duration-dependent trend of fluorescence enhancement on thepositively-charged electrode was also statistically significant for15-minute current application vs. 5- and 10-minute current application(one-way ANOVA: p<0.001, F=8.92; Holm-Sidak post-hoc analysis: p<0.01,t=3.37 for 15 minutes vs. 5 minutes and t=3.889 for 15 minutes vs. 10minutes due to nonspecific binding). At all concentrations there wassignificant attraction of the amyloid beta to the anode vs. the cathode.

These experimental results demonstrate that soluble monomeric amyloidbeta in its native conformation is negatively charged in aCSF and iscapable of moving in the electrical field without the need to add anyamphiphilic detergents to provide the negative charge to the amyloidbeta.

Amyloid Beta Electrophoretic Mobility Assessment in Wild Type MouseBrain Parenchyma

An animal experiment was performed in accordance with an application ofthe present invention. 20 three-month wild-type mice were anesthetized,and soluble fluorophore-tagged amyloid beta (1-42), HiLyte™ Fluor488-labeled, Human (AnaSpec, USA) was injected into the brain parenchyma(AP=−2, ML=0.84, DV=1.2). A first Pt—Ir electrode was implanted in brainparenchyma (AP=−2.8, ML=0.84, DV=1.5), and a second Pt—Ir electrode wasimplanted in the lateral ventricle (AP=−0.5, ML=0.84, DV=1.6). Anelectrical field generated by the current between the electrodes coveredthe amyloid beta injection focus. The current application was applied bythe repetition of single pulses. The following parameters were used:voltage: 70 V; and frequency: 1 Hz. The current application protocol wasas follows: (a) 15 minutes with a pulse duration of 1 ms; (b) 15 minuteswith a pulse duration of 10 ms; and (c) 15 minutes with a pulse durationof 100 ms. The frequency was kept constant but the duty cycle wasincreased.

Assessment of amyloid beta movement directionality in the electricalfield was conducted by using antibodies directed against 1-16 amino acidstrip of 6E10 (Catalog no. SIG-39320) to visualize the traces of amyloidbeta peptide movement in the electrical field. Tissue structure and cellnuclei were visualized by DAPI staining. Amyloid beta movementtrajectory was evaluated at different magnifications (4× and 10×).Sagittal slices were stained with antibodies against cell nuclei (blue)and amyloid beta (6E10, green), and imaged by fluorescence microscopy.

Amyloid beta movement was visualized in mouse brains to which theelectrical current was applied. The electrode inserted into the lateralventricle was positively charged, and, similarly to the in vitroexperiment described hereinabove with reference to FIG. 3, the appliedcurrent was capable of inducing amyloid beta movement.

These experimental results demonstrate that electrophoretic movement ofamyloid beta peptides is possible in the brain parenchyma with theelectrical current-application protocol used in the experiment. Thedirectionality of amyloid beta peptide movement was similar to thatobserved the in vitro experiment described hereinabove with reference toFIG. 3.

Reference is made to FIGS. 4A-G, which are schematic illustrations ofalternative configurations of system 20, in accordance with respectiveapplications of the present invention. These figures show an anteriorview of brain 52. In these applications, system 20 is configured to, inaddition to clearing the substance (e.g., the amyloid beta, the metalions, the tau protein, and/or the waste substance) from brain parenchyma50 into the CSF-filled space, to clear the substance from the CSF-filledspace (e.g., subarachnoid space 144) to superior sagittal sinus 142.These techniques may be used in combination with any of the techniquesdescribed hereinabove. For some of these techniques, control circuitry34 is configured to apply the treatment current as direct current.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to simultaneously drive electrodes to both(a) clear the substance from brain parenchyma 50 into the CSF-filledspace, and (b) clear the substance from the CSF-filled space to superiorsagittal sinus 142. For example, control circuitry 34 may be configuredto apply different respective voltages to parenchymal electrode 30, CSFelectrode 32, and a midplane treatment electrode 150, described below.For example, control circuitry 34 may be configured to apply first,second, and third voltages to parenchymal electrode 30, CSF electrode32, and midplane treatment electrode 150, respectively, the thirdvoltage more positive than the second voltage, which is in turn morepositive than first voltage. The total potential difference between thefirst and the third voltages is typically no greater than 1.2 V volt toavoid electrolysis in the vicinity of one or both of the electrodes.

For other applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to alternatingly drive sets of theelectrodes, such as (a) during a plurality of first time periods,driving parenchymal electrode 30 and CSF electrode 32, in order to clearthe substance from brain parenchyma 50 into the CSF-filled space, and(b) during a plurality of second time periods, typically not overlappingwith the first time periods, driving midplane treatment electrode 150and either CSF electrode 32 or another electrode (described below), inorder to clear the substance from the CSF-filled space to superiorsagittal sinus 142.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to clear the substance to superior sagittalsinus 142 by electroosmotically driving fluid from the CSF-filled space(e.g., subarachnoid space 144) to superior sagittal sinus 142. For someapplications, control circuitry 34 is configured to drive the fluid fromthe CSF-filled space of the brain to superior sagittal sinus 142 byconfiguring midplane treatment electrode 150 as a cathode, and CSFelectrode 32 as an anode.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to clear the substance by electrophoreticallydriving the substance from the CSF-filled space (e.g., subarachnoidspace 144) to superior sagittal sinus 142. For some applications,application of the treatment current causes a potential differencebetween the CSF-filled space and superior sagittal sinus 142, whichcauses movement of the substance from the CSF-filled space to superiorsagittal sinus 142.

For some applications, such as shown in FIG. 4A, parenchymal electrode30 is implanted in brain parenchyma 50, and CSF electrode 32 isimplanted in the CSF-filled space, such as ventricular system 54 orsubarachnoid space 144. A midplane treatment electrode 150 is disposedeither (a) in superior sagittal sinus 142 (as shown in FIG. 4A), or (b)over superior sagittal sinus 142 (configuration not shown in FIG. 4A,but shown in FIGS. 4B-G). A second CSF electrode 152 is implanted theCSF-filled space, such as ventricular system 54 (configuration not shownin FIG. 4A) or subarachnoid space 144 (as shown in FIG. 4A). Controlcircuitry 34 is activated to apply (a) a first voltage betweenparenchymal electrode 30 and CSF electrode 32, to clear the substancefrom brain parenchyma 50 into the CSF-filled space, and (b) a secondvoltage between midplane treatment electrode 150 and second CSFelectrode 152, to clear the substance from the CSF-filled space tosuperior sagittal sinus 142. This technique may be used in combinationwith the techniques described hereinbelow with reference to FIGS. 4B-G,mutatis mutandis.

Alternatively, for some applications, such as shown in FIG. 4B,parenchymal electrode 30 is implanted in brain parenchyma 50, and CSFelectrode 32 is implanted in the CSF-filled space, such as ventricularsystem 54 or subarachnoid space 144. Midplane treatment electrode 150 isdisposed either (a) in superior sagittal sinus 142 (as shown in FIG.4A), or (b) over superior sagittal sinus 142 (as shown in FIGS. 4B-G).Control circuitry 34 is activated to apply (a) a first voltage betweenparenchymal electrode 30 and CSF electrode 32, to clear the substancefrom brain parenchyma 50 into the CSF-filled space, and (b) a secondvoltage between CSF electrode 32 and midplane treatment electrode 150,to clear the substance from the CSF-filled space to superior sagittalsinus 142.

For some applications, such as shown in FIGS. 4B-C, midplane treatmentelectrode 150 is adapted to be disposed over superior sagittal sinus142. For some of these applications, midplane treatment electrode 150 isadapted to be disposed under a skull 168 of a head 174 of the subject,such as in contact with an outer surface of superior sagittal sinus 142(either under the dura mater or in contact with an outer surface of thedura mater). For others of these applications, midplane treatmentelectrode 150 is adapted to be disposed outside and in electricalcontact with skull 168. As used in the present application, including inthe claims, “over the superior sagittal sinus” means aligned with thesuperior sagittal sinus at a location more superficial than the superiorsagittal sinus, i.e., at a greater distance from a center of the head.In the configurations shown in FIGS. 4B and 4C, control circuitry 34 isconfigured to clear the substance from the CSF-filled space to superiorsagittal sinus 142, by applying a treatment current between midplanetreatment electrode 150 and CSF electrode 32. Alternatively, theplacements of midplane treatment electrode 150 shown in FIGS. 4B and 4Care used in combination with the configuration described hereinabovewith reference to FIG. 4A.

For some applications, such as shown in FIG. 4D, system 20 comprises aplurality of midplane treatment electrodes 150, such as at least 5, nomore than 20, and/or between 5 and 20 midplane treatment electrodes 150.Midplane treatment electrodes 150 are disposed either (a) in superiorsagittal sinus 142 (configuration not shown in FIG. 4D, but shown inFIG. 4A), or (b) over superior sagittal sinus 142 (as shown in FIG. 4D,or in FIG. 4B).

For any of the applications described herein, including, but not limitedto those described with reference to FIGS. 4A-G, CSF electrode 32 may beadapted to be disposed between 1 and 12 cm of a sagittal midplane 164 ofskull 168. For some applications, the method may comprise implanting CSFelectrode 32 between 1 and 12 cm of sagittal midplane 164 of skull 168.

For any of the applications described herein, including, but not limitedto those described with reference to FIGS. 4A-G, the CSF-filled spacemay be subarachnoid space 144, CSF electrode 32 may be a subarachnoidelectrode, configured to be implanted in subarachnoid space 144, andcontrol circuitry 34 may be configured to clear the substance fromsubarachnoid space 144 to superior sagittal sinus 142.

For some applications, such as shown in FIG. 4E-G, system 20 comprises(a) midplane treatment electrodes 150, adapted to be disposed oversuperior sagittal sinus 142, outside and in electrical contact withskull 168, and (b) lateral treatment electrodes 162, adapted to bedisposed at a distance of between 1 and 12 cm of sagittal midplane 164of skull 168 (the distance is measured in a straight line from a closestportion of each treatment electrode to sagittal midplane 164, ratherthan along the curvature of skull 168). Control circuitry 34 isconfigured to clear the substance from subarachnoid space 144 tosuperior sagittal sinus 142, by applying one or more treatment currentsbetween (a) one or more of midplane treatment electrodes 150 and (b) oneor more of lateral treatment electrodes 162 (each of the treatmentcurrents is schematically illustrated in the figures by a plurality ofcurrent lines 190).

For some applications, system 20 comprises as at least 5, no more than40, and/or between 5 and 40 lateral treatment electrodes 162, such asbetween 5 and 20 lateral treatment electrodes 162, or between 10 and 40lateral treatment electrodes. For some applications, the number of eachtype of treatment electrode is determined based on the size of head 174of the subject. For some applications, system 20 comprises twice as manylateral treatment electrodes 162 as midplane treatment electrodes 150.

For some applications, the one or more treatment currents applied usingmidplane treatment electrodes 150 and lateral treatment electrodes 162pass between subarachnoid space 144 and superior sagittal sinus 142, viainferolateral surfaces 170 of superior sagittal sinus 142. For some ofthese applications, at least 40%, e.g., at least 75% or at least 90%, ofthe treatment currents pass between subarachnoid space 144 and superiorsagittal sinus 142, via inferolateral surfaces 170 of superior sagittalsinus 142. For the applications described immediately above, thelocations of midplane treatment electrodes 150 and/or lateral treatmentelectrodes 162 are typically selected such that the one or moretreatment currents pass through inferolateral surfaces 170. For example,for configurations in which lateral treatment electrodes 162 aredisposed outside and in electrical contact with skull 168, such asdescribed with reference to FIGS. 4C-G, lateral treatment electrodes 162may be disposed at a distance of least 4 cm, no more than 12 cm, and/orbetween 4 and 12 cm of sagittal midplane 164 of skull 168; forconfigurations in which lateral treatment electrodes 162 are implantedunder an arachnoid mater 172 of the subject, such as described withreference to FIGS. 4C-G, lateral treatment electrodes 162 may bedisposed at least 1 cm, no more than 3 cm, and/or between 1 and 3 cm ofsagittal midplane 164 of skull 168.

For some applications, at least five midplane treatment electrodes 150are disposed over superior sagittal sinus 142. Alternatively oradditionally, for some applications, at least five lateral treatmentelectrodes 162 between 1 and 12 cm of sagittal midplane 164 of skull168. For some applications, each of lateral treatment electrodes 162 isdisposed between 1 and 12 cm of at least one of midplane treatmentelectrodes 150.

For some applications, midplane treatment electrodes 150 are disposedwithin 10 mm of sagittal midplane 164 of skull 168. Alternatively oradditionally, for some applications, midplane treatment electrodes 150are disposed such that at least one of midplane treatment electrodes 150is at least 5 mm from another one of midplane treatment electrodes 150,no more than 20 mm from another one of midplane treatment electrodes150, and/or between 5 and 150 mm from another one of midplane treatmentelectrodes 150. For some applications, at least one of lateral treatmentelectrodes 162 is disposed is at least 5 mm from another one of lateraltreatment electrodes 162.

For some applications, such as shown in FIG. 4E, midplane treatmentelectrodes 150 are implanted under skin 176 of head 174. For otherapplications, such as shown in FIG. 4F, midplane treatment electrodes150 are disposed outside head 174, such as on an external surface 178 ofhead 174.

For some applications, system 20 further comprises a midplane lead 180,along which midplane treatment electrodes 150 are disposed (e.g.,fixed). Midplane lead 180 is disposed outside skull 168 in order todispose midplane treatment electrodes 150 over superior sagittal sinus142. For some applications in which midplane treatment electrodes 150are implanted under skin 176, the implantation is performed byintroducing midplane lead 180 through an incision in skin 176, typicallyat a posterior site of the head, and tunneling the midplane lead towardan anterior site of the head, such as near the forehead. Optionally,each of midplane treatment electrodes 150 is inserted through arespective incision in skin 176, and connected to midplane lead 180.

For some applications, such as shown in FIGS. 4E-F, lateral treatmentelectrodes 162 are disposed outside and in electrical contact with skull168. For some of these applications, lateral treatment electrodes 162are implanted under skin 176 of head 174, such as shown in FIG. 4E.Alternatively, lateral treatment electrodes 162 are disposed outsidehead 174, such as on external surface 178 of head 174, such as shown inFIG. 4F. For some of these applications, lateral treatment electrodes162 may be disposed at least 4 cm, no more than 12 cm, and/or between 4and 12 cm of sagittal midplane 164 of skull 168. (As used in the presentapplication, including in the claims, all specified ranges include theirendpoints.) Such positioning may generate one or more treatment currentsthat pass between subarachnoid space 144 and superior sagittal sinus142, via inferolateral surfaces 170 of superior sagittal sinus 142, asdescribed above.

For some applications, system 20 further comprises a lateral lead 182,along which lateral treatment electrodes 162 are disposed (e.g., fixed).Lateral lead 182 is disposed outside skull 168, typically within 1 and12 cm of sagittal midplane 164 of skull 168, in order to dispose lateraltreatment electrodes 162. For some applications in which lateraltreatment electrodes 162 are implanted under skin 176, the implantationis performed by introducing lateral lead 182 through an incision in skin176, typically at a posterior site of the head, and tunneling thelateral lead toward an anterior site of the head, such as near theforehead. Optionally, each of lateral treatment electrodes 162 isinserted through a respective incision in skin 176, and connected tolateral lead 182. For some applications, instead of providing laterallead 182, lateral treatment electrodes 162 are instead coupled tomidplane lead 180. Midplane lead 180 is introduced with the lateralelectrodes constrained, and, the lateral electrodes are configured uponrelease to extend laterally, typically automatically. This configurationmay also be used for applications in which both left and right lateralelectrodes are provided, as described hereinbelow.

For some applications, control circuitry 34 is activated toindependently apply the treatment currents between respective pairs ofmidplane treatment electrodes 150 and lateral treatment electrodes 162.Such independent application of the currents allows continued effectiveoperation of system 20 even if a low resistance should develop betweenthe electrodes of one of the pairs (e.g., because of anatomicalvariations). For some of these applications, in order to enable suchindependent application of the currents, midplane lead 180 comprises aplurality of conductive wires corresponding to a number of midplanetreatment electrodes 150, and lateral lead 182 comprises a plurality ofconductive wires corresponding to a number of lateral treatmentelectrodes 162. Alternatively, control circuitry 34 and the electrodesimplement electrical multiplexing, as is known in the art, in which caseeach of the leads need only comprise a single conductive wire.Alternatively, for some applications, all of midplane treatmentelectrodes 150 are electrically coupled to one another (such as by asingle conductive wire in the midplane lead), and all of lateraltreatment electrodes 162 are electrically coupled to one other (such asby a single conductive wire in the lateral lead).

For some applications of the configuration shown in FIG. 4F, system 20further comprises one or more thin elongate support elements 184, whichcouple lateral leads 182 to midplane lead 180, in order to provideproper spacing and alignment between the midplane electrodes and thelateral electrodes. Support elements 184 are typically non-conductive.

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is configured to apply the one or more treatment currentswith an average amplitude of between 1 and 3 milliamps. (The resultingvoltage is typically greater in the configuration shown in FIGS. 4E-Fthan in the configuration shown in FIG. 4G, because the one or moretreatment currents pass through skull 168 twice.)

For some applications described with reference to FIGS. 4A-G, controlcircuitry 34 is activated to apply the one or more treatment currents asdirect current, typically as a plurality of pulses, for example atgreater than 500 Hz and/or less than 2 kHz, e.g., at 1 kHz. For someapplications, a duty cycle of the pulses is above 90%, and for someapplications pulses are not used but instead an effective duty cycle of100% is utilized. Typically, but not necessarily, the duty cycle is 90%or lower, because a given level of applied voltage produces highercurrent in the tissue if the capacitance in the tissue is allowed todischarge between pulses. For other applications, control circuitry 34is activated to apply the one or more treatment currents as alternatingcurrent with a direct current offset and a constant polarity. Forexample, the frequency may be at least 1 Hz, no more than 100 Hz (e.g.,no more than 10 Hz), and/or between 1 Hz and 100 Hz (e.g., between 1 Hzand 10 Hz).

As mentioned above, for some applications, control circuitry 34 isconfigured to clear the substance by electroosmotically driving fluidfrom subarachnoid space 144 to superior sagittal sinus 142. For someapplications, control circuitry 34 is configured to configure midplanetreatment electrodes 150 as cathodes, and lateral treatment electrodes162 as anodes. Alternatively or additionally, increased flow ofcerebrospinal fluid (CSF) out of the brain's ventricular system viasubarachnoid space 144, as a result of the applied voltage, may itselftreat Alzheimer's disease and/or CAA, independent of any directclearance of beta amyloid in the CSF flow.

For some applications, lateral treatment electrodes 162 comprise (a)left lateral treatment electrodes 162A, which are adapted to be disposedleft of sagittal midplane 164 of skull 168, and (b) right lateraltreatment electrodes 162B, which are adapted to be disposed right ofsagittal midplane 164 of skull 168. For some applications, controlcircuitry 34 is configured to configure midplane treatment electrodes150 as cathodes, and left and right lateral treatment electrodes 162Aand 162B as left and right anodes, respectively.

As mentioned above, for some applications, control circuitry 34 isconfigured to clear the substance by electrophoretically driving thesubstance from subarachnoid space 144 to superior sagittal sinus 142.For some applications, lateral treatment electrodes 162 comprise (a)left lateral treatment electrodes 162A, which are adapted to be disposedleft of sagittal midplane 164 of skull 168, and (b) right lateraltreatment electrodes 162B, which are adapted to be disposed right ofsagittal midplane 164 of skull 168. For some of these applications,control circuitry 34 is configured to configure the midplane treatmentelectrodes 150 as anodes, and left and right lateral treatmentelectrodes 162A and 162B as left and right cathodes, respectively. Inexperiments conducted on behalf of the inventor, amyloid beta was foundto be attracted to the positive electrode (anode).

For some applications, lateral treatment electrodes 162 are adapted tobe implanted under an arachnoid mater 172 of the subject, such as inbrain parenchyma 50 (gray or white matter), as shown in FIG. 4G, or insubarachnoid space 144, such as shown in FIG. 4A. For some applications,the same electrodes serve as both parenchymal electrode 30 and lateraltreatment electrodes 162, and are driven by control circuitry 34 eitherat the same time or at different times. For example, lateral treatmentelectrodes 162 may comprise needle electrodes, as is known in the art;optionally, lateral treatment electrodes 162 comprise respectiveproximal anchors 188. This configuration may implement any of thetechniques described hereinabove with reference to FIGS. 4A-F, mutatismutandis.

For some of these applications, lateral treatment electrodes 162 aredisposed at least 1 cm, no more than 3 cm, and/or between 1 and 3 cm ofsagittal midplane 164 of skull 168. Such positioning may generate thetreatment currents that pass between subarachnoid space 144 and superiorsagittal sinus 142, via inferolateral surfaces 170 of superior sagittalsinus 142, as described above. For some applications, each of lateraltreatment electrodes 162 is disposed between 1 and 3 cm of at least oneof midplane treatment electrodes 150. For some applications, each oflateral treatment electrodes 162 is disposed between 1 and 3 cm of oneof midplane treatment electrodes 150 that is closest to the lateraltreatment electrode.

As mentioned above, for some applications, system 20 further comprisesmidplane lead 180, along which midplane treatment electrodes 150 aredisposed (e.g., fixed). Midplane lead 180 is disposed outside skull 168in order to dispose midplane treatment electrodes 150. For some of theseapplications, system 20 further comprises (a) a left lateral lead 182A,along which left lateral treatment electrodes 162A are disposed (e.g.,fixed), and (b) a right lateral lead 182B, along which right lateraltreatment electrodes 162B are disposed (e.g., fixed). Left lateral lead186A is disposed outside skull 168, typically within 1 and 12 cm ofsagittal midplane 164 of skull 168, in order to dispose left lateraltreatment electrodes 162A. Right lateral lead 186B is disposed outsideskull 168, typically within 1 and 12 cm of sagittal midplane 164 ofskull 168, in order to dispose right lateral treatment electrodes 162B.

Reference is again made to 4A-G. For some applications, controlcircuitry 34 is configured to detect a voltage difference betweensubarachnoid space 144 and superior sagittal sinus 142, and set a levelof the one or more treatment currents responsively to the detectedvoltage difference.

Although some of the techniques described hereinabove have beendescribed as treating the subject by electroosmotically driving fluidfrom subarachnoid space 144 to superior sagittal sinus 142, thetechniques may alternatively or additionally be used withoutelectroosmosis.

The scope of the present invention includes embodiments described in thefollowing applications, which are assigned to the assignee of thepresent application and are incorporated herein by reference. In anembodiment, techniques and apparatus described in one or more of thefollowing applications are combined with techniques and apparatusdescribed herein:

-   -   U.S. application Ser. No. 13/872,794, filed Apr. 20, 2013, which        published as US Patent Application Publication 2014/0324128;    -   U.S. application Ser. No. 14/794,739, filed Jul. 8, 2015, which        issued as U.S. Pat. No. 9,616,221;    -   International Application PCT/IL2016/050728, filed Jul. 7, 2016,        which published as PCT Publication WO 2017/006327; and    -   U.S. application Ser. No. 14/926,705, filed Oct. 29, 2015, which        issued as U.S. Pat. No. 9,724,515.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

The invention claimed is:
 1. A method comprising: implanting aparenchymal electrode in or in contact with an outer surface of brainparenchyma of a subject identified as at risk of or suffering from adisease; implanting a cerebrospinal fluid (CSF) electrode in aCSF-filled space of a brain of the subject, the CSF-filled spaceselected from the group consisting of: a ventricular system and asubarachnoid space; disposing a midplane treatment electrode in or overa superior sagittal sinus; and activating control circuitry to: drivethe parenchymal electrode and the CSF electrode to drive a substancefrom the brain parenchyma into the CSF-filled space of the brain byapplying direct current between the parenchymal electrode and the CSFelectrode with an average amplitude of between 1 and 5 mA, the substancecomprising one or more substances selected from the group of substancesconsisting of: amyloid beta, tau protein, and metal ions, and applytreatment direct current, with an average amplitude of between 1 and 3mA, between the CSF electrode and the midplane treatment electrode todrive the substance from the CSF-filled space of the brain to thesuperior sagittal sinus.
 2. The method according to claim 1, wherein thedisease is Alzheimer's disease, and wherein implanting parenchymalelectrode comprises implanting the parenchymal electrode in the subjectidentified as at risk of or suffering from Alzheimer's disease.
 3. Themethod according to claim 1, wherein the disease is cerebral amyloidangiopathy (CAA), and wherein implanting parenchymal electrode comprisesimplanting the parenchymal electrode in the subject identified as atrisk of or suffering from CAA.
 4. The method according to claim 1,wherein the CSF-filled space of the brain is the ventricular system,wherein the CSF electrode is a ventricular electrode, and whereinactivating the control circuitry comprises activating the controlcircuitry to drive the parenchymal electrode and the ventricularelectrode to drive the substance from the brain parenchyma into theventricular system.
 5. The method according to claim 1, wherein theCSF-filled space of the brain is the subarachnoid space, wherein the CSFelectrode is a subarachnoid electrode, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal electrode and the subarachnoid electrode to drive thesubstance from the brain parenchyma into the subarachnoid space.
 6. Themethod according to claim 1, wherein the substance includes amyloidbeta, and wherein activating the control circuitry comprises activatingthe control circuitry to drive the parenchymal electrode and the CSFelectrode to drive the amyloid beta from the brain parenchyma into theCSF-filled space of the brain.
 7. The method according to claim 1,wherein the substance includes metal ions, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal electrode and the CSF electrode to drive the metal ionsfrom the brain parenchyma into the CSF-filled space of the brain.
 8. Themethod according to claim 1, wherein the substance includes tau protein,and wherein activating the control circuitry comprises activating thecontrol circuitry to drive the parenchymal electrode and the CSFelectrode to drive the tau protein from the brain parenchyma into theCSF-filled space of the brain.
 9. The method according to claim 1,wherein implanting the parenchymal electrode in or in contact with theouter surface of the brain parenchyma comprises implanting theparenchymal electrode in contact with the outer surface of the brainparenchyma.
 10. The method according to claim 1, wherein implanting theparenchymal electrode in or in contact with the outer surface of thebrain parenchyma comprises implanting the parenchymal electrode in thebrain parenchyma.
 11. The method according to claim 10, whereinimplanting the parenchymal electrode and the CSF electrode comprisesimplanting the parenchymal electrode and the CSF electrode such that anarea of build-up of the substance is between the parenchymal and the CSFelectrodes.
 12. The method according to claim 10, wherein implanting theparenchymal electrode comprises implanting the parenchymal electrodesuch that an area of build-up of the substance is between theparenchymal electrode and an area of the CSF-filled space of the brainnearest the area of build-up.
 13. The method according to claim 1,further comprising applying deep brain stimulation using the parenchymalelectrode.
 14. The method according to claim 1, wherein activating thecontrol circuitry to drive the parenchymal electrode and the CSFelectrode comprises activating the control circuitry to drive theparenchymal electrode and the CSF electrode to drive the substance byapplying the direct current as non-excitatory current between theparenchymal electrode and the CSF electrode.
 15. The method according toclaim 1, wherein activating the control circuitry to apply the directcurrent comprises activating the control circuitry to apply the directcurrent with an average voltage of less than 1.2 V.
 16. The methodaccording to claim 1, wherein activating the control circuitry to applythe direct current comprises activating the control circuitry to applythe direct current as a series of pulses at a frequency of between 1 and10 Hz.
 17. The method according to claim 1, wherein disposing themidplane treatment electrode comprises disposing the midplane treatmentelectrode over the superior sagittal sinus, outside and in electricalcontact with a skull of a head of the subject.
 18. The method accordingto claim 1, wherein disposing the midplane treatment electrode comprisesimplanting the midplane treatment electrode in the superior sagittalsinus.
 19. The method according to claim 1, wherein the CSF-filled spaceof the brain is the subarachnoid space, wherein the CSF electrode is asubarachnoid electrode, and wherein activating the control circuitrycomprises activating the control circuitry to drive the substance fromthe subarachnoid space to the superior sagittal sinus.
 20. The methodaccording to claim 1, wherein activating the control circuitry comprisesactivating the control circuitry to drive the parenchymal electrode andthe CSF electrode to drive the substance from the brain parenchyma intothe CSF-filled space of the brain by electrophoretically driving thesubstance from the brain parenchyma into the CSF-filled space of thebrain.
 21. The method according to claim 1, wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe substance from the CSF-filled space of the brain to the superiorsagittal sinus by electrophoretically driving the substance from theCSF-filled space of the brain to the superior sagittal sinus.
 22. Themethod according to claim 1, wherein activating the control circuitrycomprises activating the control circuitry to drive the parenchymalelectrode and the CSF electrode to drive the substance from the brainparenchyma into the CSF-filled space of the brain by electroosmoticallydriving fluid from the brain parenchyma into the CSF-filled space of thebrain.
 23. The method according to claim 1, wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe substance from the CSF-filled space of the brain to the superiorsagittal sinus by electroosmotically driving fluid from the CSF-filledspace of the brain to the superior sagittal sinus.
 24. The methodaccording to claim 1, wherein activating the control circuitry comprisesactivating the control circuitry to simultaneously drive (a) theparenchymal electrode and the CSF electrode to drive the substance fromthe brain parenchyma into the CSF-filled space of the brain, and (b)apply the treatment direct current between the midplane treatmentelectrode and the CSF electrode to drive the substance from theCSF-filled space to the superior sagittal sinus.
 25. The methodaccording to claim 24, wherein activating the control circuitrycomprises activating the control circuitry to apply first, second, andthird voltages to the parenchymal electrode, the CSF electrode, and themidplane treatment electrode, respectively, the third voltage morepositive than the second voltage, which is in turn more positive thanfirst voltage.
 26. The method according to claim 1, wherein activatingthe control circuitry comprises activating the control circuitry toalternatingly (a) drive the parenchymal electrode and the CSF electrodeto drive the substance from the brain parenchyma into the CSF-filledspace of the brain, and (b) apply the treatment direct current betweenthe midplane treatment electrode and the CSF electrode to drive thesubstance from the CSF-filled space to the superior sagittal sinus. 27.A method comprising: implanting a parenchymal electrode in or in contactwith an outer surface of brain parenchyma of a subject identified as atrisk of or suffering from a disease; implanting a first cerebrospinalfluid (CSF) electrode in a CSF-filled space of a brain of the subject,the CSF-filled space selected from the group consisting of: aventricular system and a subarachnoid space; implanting a second CSFelectrode in a CSF-filled space of a brain of the subject, theCSF-filled space selected from the group consisting of: the ventricularsystem and the subarachnoid space; disposing a midplane treatmentelectrode in or over a superior sagittal sinus; and activating controlcircuitry to: drive the parenchymal electrode and the first CSFelectrode to drive a substance from the brain parenchyma into theCSF-filled space of the brain, by applying direct current between theparenchymal electrode and the CSF electrode with an average amplitude ofbetween 1 and 5 mA, the substance comprising one or more substancesselected from the group of substances consisting of: amyloid beta, tauprotein, and metal ions, and apply treatment direct current, with anaverage amplitude of between 1 and 3 mA, between the second CSFelectrode and the midplane treatment electrode to drive the substancefrom the CSF-filled space of the brain to the superior sagittal sinus.28. The method according to claim 27, wherein disposing the midplanetreatment electrode comprises disposing the midplane treatment electrodeover the superior sagittal sinus, outside and in electrical contact witha skull of a head of the subject.
 29. The method according to claim 27,wherein disposing the midplane treatment electrode comprises implantingthe midplane treatment electrode in the superior sagittal sinus.
 30. Themethod according to claim 27, wherein the substance includes amyloidbeta, and wherein activating the control circuitry comprises activatingthe control circuitry to drive the parenchymal electrode and the firstCSF electrode to drive the amyloid beta from the brain parenchyma intothe CSF-filled space of the brain, and to apply the treatment directcurrent between the second CSF electrode and the midplane treatmentelectrode to drive the amyloid beta from the CSF-filled space of thebrain to the superior sagittal sinus.
 31. The method according to claim27, wherein the substance includes metal ions, and wherein activatingthe control circuitry comprises activating the control circuitry todrive the parenchymal electrode and the first CSF electrode to drive themetal ions from the brain parenchyma into the CSF-filled space of thebrain, and to apply the treatment direct current between the second CSFelectrode and the midplane treatment electrode to drive the metal ionsfrom the CSF-filled space of the brain to the superior sagittal sinus.32. The method according to claim 27, wherein the substance includes tauprotein, and wherein activating the control circuitry comprisesactivating the control circuitry to drive the parenchymal electrode andthe first CSF electrode to drive the tau protein from the brainparenchyma into the CSF-filled space of the brain, and to apply thetreatment direct current between the second CSF electrode and themidplane treatment electrode to drive the tau protein from theCSF-filled space of the brain to the superior sagittal sinus.